Natural killer (NK) cells are a sub-population of lymphocytes that are involved in non-conventional immunity. Characteristics and biological properties of NK cells include the expression of surface antigens such as CD16, CD56 and/or CD57, and the absence of the alpha/beta or gamma/delta TCR complex expressed on the cell surface; the ability to bind to and kill cells that fail to express “self” MHC/HLA antigens by the activation of specific cytolytic enzymes; the ability to kill tumor cells or other diseased cells that express a NK activating receptor-ligand; and the ability to release protein molecules called cytokines that stimulate or inhibit the immune response.
NK cell activity is regulated by a complex mechanism that involves both activating and inhibitory signals. Several distinct classes of NK-specific receptors have been identified that play an important role in the NK cell mediated recognition and killing of HLA Class I deficient target cells. One such class of receptors, the NCRs (for Natural Cytotoxicity Receptors), includes NKp30, NKp46 and NKp44, all members of the Ig superfamily. Their cross-linking, induced by specific mAbs, strongly activates NK cells, resulting in increased intracellular Ca++ levels, triggering of cytotoxicity, and lymphokine release.
Two additional families of NK cell receptors are the KIR receptors (Killer Cell Immunoglobulin-like Receptors) and CD94/NKG2. Each of these families contain both activating and inhibitory receptors. KIR genes represent a diverse, polymorphic group of Ig superfamily members expressed on NK cells and having either two or three extracellular Ig-like domains. The cytoplasmic domains of the inhibitory members of the family, including KIR2DL1, KIR2DL2, KIR2DL3, KIR2DL5A, KIR2DL5B, KIR3DL1, KIR3DL2, and KIR3DL3, contain ITIM sequences, in contrast to the cytoplasmic domains of the activating members, such as KIR2DS1, KIR2DS2, KIR2DS3, KIR2DS4, KIR2DS5, and KIR3DS1, which usually contain a charged residue. Inhibitory members of the KIR family mediate the inhibitory effect HLA class 1 molecules. The polymorphism seen within the KIR receptor family is a result of genetic variation between individuals as well as the clonal expansion of particular NK cells in vivo. For review see, e.g., Trowsdale and Parham (2004) Eur J Immunol 34(1):7-17; Yawata et al. (2002) Crit Rev Immunol 22(5-6):463-82; Hsu et al. (2002) Immunol Rev 190:40-52; Middleton et al. (2002) Transpl Immunol 10(2-3):147-64; Vilches et al. (2002) Annu Rev Immunol 20:217-51.
CD94 and NKG2 proteins are members of the C-type lectin superfamily. CD94 is preferentially expressed on NK cells, and forms heterodimers with NKG2 family members, such as NKG2A, which is itself expressed on at least 50% of all NK cells. NKG2A contains 2 ITIM domains, and together with CD94 forms a heterodimeric inhibitory receptor that binds to nonclassical MHC class 1 molecule HLA-E (in humans; Qa-1b in mice) (see, e.g., OMIM 602894; Braud et al. (1998) Nature 391:795-799; Chang et al. (1995) Europ. J. Immun 25:2433-2437; Lazetic et al. (1996) Immun 157:4741-4745; Rodriguez et al. (1998) Immunogenetics 47:305-309.)
NK-LDGL (NK-type lymphoproliferative disease of granular lymphocytes; alternatively called NK-LGL) refers to a class of proliferative disorders that is caused by the clonal expansion of NK cells or NK-like cells, i.e., large granular lymphocytes showing a characteristic combination of surface antigen expression (e.g., CD3−, CD56+, CD16+, etc.; see, e.g., Loughran (1993) Blood 82:1). The cell proliferation underlying these disorders can have variable effects, ranging from the mild symptoms seen in some patients to the aggressive, often-fatal form of the disease called NK-LDGL leukemia. Symptoms of this class of disorders can include fever, mild neutropenia, thrombocytopenia, anemia, lymphocytosis, splenomegaly, hepatomegaly, lymphadenopathy, marrow infiltration, and others (see, e.g., Zambello et al. (2003) Blood 102:1797; Loughran (1993) Blood 82:1; Epling-Burnette et al. (2004) Blood-2003-02-400). Treatment for NK-LDGL leukemia is often aggressive, involving chemotherapy, and the disease is often fatal, associated with coagulopathy and multiple organ failure, and involving LGL infiltration of numerous organs. Autoimmune disorders are also prominent in LDGL and numerous disorders are observed including foremost rheumatoid arthritis and increased numbers of cells with a LDGL leukemic phenotype have been found in the blood or synovial fluid of rheumatoid arthritis patients. Some of these expanded cells are CD28 negative T cells having functional and phenotypical characteristics of LGL. Also observed in LDGL patients are idiopathic thrombocytopenic purpura (ITP) and aplastic anemia. Therapies useful in the treatment of NK-LDGL and LDGL generally are therefore expected to have use in the treatment of immunoproliferative and autoimmune conditions as well, particularly disorders where NK cells are implicated.
Generally, few effective therapies are effective for the treatment of established immune disorders. For example, in the case of rheumatoid arthritis, once triggered, the immune response causes inflammation of the synovium. Early and intermediate molecular mediators of inflammation include tumor necrosis factor alpha (TNF-α), interleukins IL-1, IL-6, IL-8 and IL-15, transforming growth factor beta, fibroblast growth factor and platelet-derived growth factor. Modern pharmacological treatments of RA target these mediators but do not remove the underlying cells, particularly when the cells involved are NK cells. Once the inflammatory reaction is established, the synovium thickens, the cartilage and the underlying bone begins to disintegrate and evidence of joint destruction accrues. In view of the relative dearth of effective treatments for immunoproliferative disorders, it is clear that there is a great need in the art for new and innovative strategies for limiting and reversing the immune cells activation and/or proliferation that underlies these disorders. The present invention addresses these and other needs.